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Department of Neurobiology and Physiology (M.I.S., D.M.B., T.K.W.), Northwestern University, Evanston, Illinois 60208; Department of Medicine (T.K.W.), Northwestern Medical School, Chicago, Illinois 60611; and Department of Medical and Molecular Genetics and the Walther Oncology Center (Y.C.), Indiana University School of Medicine, Indianapolis, Indiana 46202
Address all correspondence and requests for reprints to Teresa K. Woodruff, Ph.D., Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, Illinois 60208. E-mail: tkw{at}northwestern.edu.
Synthesis of FSH by the anterior pituitary is regulated by activin, a member of the TGFß superfamily of ligands. Activin signals through a pathway that involves the activation of the transcriptional coregulators Smad2 and Smad3. Previous work from our laboratory demonstrated that Smad3, and not Smad2, is sufficient for stimulation of the rat FSHß promoter in a pituitary-derived cell line LßT2. Here, we used RNA interference technology to independently decrease the expression of Smad proteins in LßT2 cells to further investigate Smad2 and Smad3 roles in activin-dependent regulation of the FSHß promoter. Down-regulation of Smad2 protein by small interfering RNA duplexes affects only basal transcription of FSHß, whereas decreased expression of Smad3 abrogates activin-mediated stimulation of FSHß transcription.
Although highly related, Smad2 and Smad3 differ in their Mad homolog (MH) 1 domains, where the Smad2 protein contains two additional stretches of amino acids that prevent this factor from binding to DNA. We investigated whether these structural features contribute to differential FSHß transactivation by Smad2 and Smad3. A variety of Smad chimera constructs were generated and used in transient transfection studies to address this question. Only cotransfection of chimera constructs that contain the MH1 domain of Smad3 results in activin-mediated stimulation of the rat FSHß promoter. Furthermore, the insertion of Smad2 loops into Smad3 protein renders it inactive, suggesting that DNA binding is necessary for Smad3-mediated stimulation of the rat FSHß promoter. Taken together, these results indicate that the functional differences between Smad2 and Smad3 in their ability to transactivate the rat FSHß promoter lie primarily within the MH1 domain and involve structural motifs that affect DNA binding.
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